The decrease of acetylcholine receptors at neuromuscular junctions of myasthenic patients has been attributed to an antibody-mediated autoimmune process that accelerates receptor degradation. We studied the mechanism of this process in skeletal-muscle cultures, using intact antibodies and antibody fragments. Addition of myasthenic IgG or its divalent fragment, F(ab′)2, to cultures accelerated the rate of acetylcholine-receptor degradation threefold. By contrast, the monovalent fragment, Fab, from myasthenic serum had no effect on degradation, although it bound to acetylcholine receptors. Addition of a second, “piggyback” antibody to cross-link the Fab:receptor complexes resulted in a threefold increase of the degradation rate. Similarly, when acetylcholine receptors with bound α-bungarotoxin were cross-linked by the addition of specific antibody against α-bungarotoxin, the degradation rate increased approximately threefold. The effect of myasthenic patients’ antibodies in accelerating degradation of acetylcholine receptors is attributed to their ability to cross-link the receptors. (N Engl J Med 298:1116–1122, 1978) MYASTHENIA gravis is a neuromuscular disorder characterized by weakness and fatigability of muscles. It is now well established that there is a decrease of acetylcholine receptors at neuromuscular junctions of myasthenic patients,1 2 3 4 5 sufficient to account for the typical clinical and electrophysiologic manifestations of the disorder.6 Abundant evidence indicates that the pathogenesis of myasthenia gravis involves an autoimmune attack directed against acetylcholine receptors (reviewed by Drachman7 and Lennon8). A humoral immune mechanism has been implicated in myasthenia by the finding of circulating antibodies against acetylcholine receptor9 10 11 capable of reproducing the basic features of the disease on passive transfer to mice.
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